Ann Thorac Surg 2012;93:559-564. doi:10.1016/j.athoracsur.2011.10.058
© 2012 The Society of Thoracic Surgeons
Original Articles: Adult Cardiac
Impact of Preoperative Angiotensin-Converting Enzyme Inhibitor Use on Clinical Outcomes After Cardiac Surgery
Maral Ouzounian, MDa,*,
Karen J. Buth, MSa,
Liliya Valeeva, MDa,
Craig C. Morton, MSa,
Ansar Hassan, MD, PhDb,
Imtiaz S. Ali, MDa
a Division of Cardiac Surgery, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
b Department of Cardiac Surgery, New Brunswick Heart Centre, Saint John Regional Hospital, Saint John, New Brunswick, Canada
Accepted for publication October 20, 2011.
* Address correspondence to Dr Ouzounian, Queen Elizabeth II Health Sciences Centre, 1796 Summer St, Rm 2263, Halifax, Nova Scotia, B3H 3A7, Canada (Email: mouzouni{at}dal.ca).
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Abstract
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Background: Controversy exists about whether preoperative angiotensin-converting enzyme inhibitor (ACEi) therapy is associated with adverse outcomes after coronary artery bypass grafting (CABG).
Methods: We analyzed the outcomes of consecutive patients who underwent isolated CABG between 1998 and 2007 at a single institution. We used multivariable models to examine the association between preoperative ACEi therapy and in-hospital and long-term outcomes.
Results: Of the 5946 patients undergoing isolated CABG during the study period, 3,262 (54.9%) were treated with an ACEi preoperatively and 2,684 (45.1%) were not. Median follow-up was 3.8 years. Patients treated with an ACEi preoperatively were more likely to have diabetes, hypertension, an ejection fraction of less than 40%, and recent myocardial infarction (all p < 0.0001). They were less likely to have pre-existing renal failure (p = 0.004) or require an urgent or emergent CABG (p = 0.03). Postoperative use of an inotrope (26% vs 20%, p < 0.0001) or intra-aortic balloon pump (1.8% vs 1.1%, p = 0.03) was more frequent in patients treated preoperatively with an ACEi; however, preoperative ACEi use was not an independent predictor of in-hospital mortality (odds ratio [OR], 1.1; p = 0.76), prolonged length of stay in the intensive care unit (OR, 0.9; p = 0.09), or new-onset renal failure (OR, 0.7; p = 0.09). Furthermore, preoperative use of an ACEi had no independent association with long-term survival (p = 0.54) or freedom from acute coronary syndrome (p = 0.07). However, it was associated with an increased risk of readmission for heart failure over time (hazard ratio, 1.2; p = 0.007).
Conclusions: We found no association between preoperative ACEi therapy and adverse in-hospital outcomes or long-term survival after CABG. Preoperative ACEi therapy appears to be safe in patients undergoing CABG.
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Introduction
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Angiotensin-converting enzyme inhibitors (ACEi) are known to have a multitude of beneficial effects in patients with cardiovascular disease. Early ACEi therapy confers a survival benefit by limiting the extent of adverse ventricular remodeling in patients with myocardial infarction (MI) and left ventricular dysfunction [1]. Similarly, ACEi therapy appears to decrease mortality and improve end-organ function in patients who have coronary artery disease without left ventricular dysfunction and heart failure [2].
To date, little is known about the effects of ACEi in patients undergoing cardiac surgery. Although ACEi have been thought to potentially mitigate the deleterious effects of cardiopulmonary bypass (CPB) and the ischemia-reperfusion injury coincident with aortic cross-clamping [3], the published literature about ACEi is contradictory, with their perioperative use in cardiac surgical patients having been associated with both beneficial [4] and harmful [5] effects. The purpose of the present study was to examine the effects of preoperative ACEi use on the in-hospital and long-term outcomes of a contemporary cohort of patients undergoing isolated coronary artery bypass grafting (CABG).
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Patients and Methods
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Study Sample
All patients who underwent isolated CABG at the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, between July 1, 1998 and March 31, 2007 were identified through the Maritime Heart Center Cardiac Surgery Registry. To facilitate linkage with administrative longitudinal data, the study population was restricted to patients residing in Nova Scotia at the time of surgery and who were eligible for provincial health insurance coverage.
Approval from the institutional research ethics board of the Queen Elizabeth II Health Sciences Centre (the "Capital Health Research Ethics Board") was obtained before the study. The data were stripped of all personal identifiers before being used in statistical analysis, to ensure patient anonymity and confidentiality.
Data Collection and Variable Definitions
The Maritime Heart Center Cardiac Surgery Registry is a detailed clinical registry that has prospectively collected perioperative data on all patients undergoing cardiac surgery at the Queen Elizabeth II Health Sciences Centre from March 1, 1995 until the present. For the purposes of examining long-term survival and readmission to the hospital, clinical data from the registry have been linked to government-based administrative data from Nova Scotia Vital Statistics and the Canadian Institute for Health Information discharge abstract data bases provided by the Population Health Research Unit at Dalhousie University.
Preoperative clinical variables included in the study were age, gender, diabetes, smoking history, renal failure, hypercholesterolemia, hypertension, ejection fraction < 40%; history of MI within 21 days preceding surgery, cerebrovascular or peripheral vascular disease, chronic obstructive pulmonary disease (COPD), and history of heart failure; coronary disease burden, urgency of surgery, and preoperative medical therapy (nitrates, statins, β-blockers, angiotensin-converting enzyme [ACE] inhibitors). Intraoperative variables of interest included the number of bypasses, cross-clamp time, total bypass time, and whether or not the patient left the operating room while being treated with an inotropic agent or had intra- or postoperative placement of an intra-aortic balloon pump (IABP).
The primary outcome of interest was in-hospital mortality. Other in-hospital outcomes considered included perioperative MI, stroke (neurologic deficit persisting at hospital discharge), new-onset renal failure (creatinine exceeding 176 μmol/L and showing more than a 50% increase from its preoperative level), prolonged length of stay (more than 72 hours) in the intensive care unit (ICU), and postoperative length of hospital stay. The long-term outcomes of interest included all-cause mortality and readmission to the hospital for heart failure or acute coronary syndrome as defined by the International Classification of Diseases Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes (see Appendix 1 at www.cdha.nshealth.ca/discovery-innovation/documents).
Statistical Analysis
Patients who underwent CABG with and without preoperative ACEi therapy were compared through the use of Student's t-tests or Wilcoxon's rank sum tests for continuous variables and 
2 or Fisher's exact tests for categorical variables. To satisfy the assumption of linearity inherent in logistic regression and Cox proportional hazards modeling, age was transformed through the use of a restricted cubic spline function with three knots placed at the 10th, 50th, and 90th percentiles of the distribution [6].
The association of clinical characteristics with each outcome was assessed univariately. For in-hospital outcomes, 2 tests were applied to candidate categorical variables, and for longitudinal outcomes univariate Cox proportional hazards analysis was performed. Variables for multivariate analysis were selected on the basis of univariate associations with values of p < 0.2. Additional variables deemed clinically important were included in the models regardless of the univariate p value. Multi-collinearity was assessed through linear regression analysis. If the variance inflation factor exceeded 2.5, correlated variables were either combined into a single variable or only one variable from a set of correlated variables was included in the model.
Nonparsimonious logistic regression models were used to examine the association of preoperative ACEi use and in-hospital mortality, new-onset renal failure, and prolonged stay in the ICU, after adjustment for preoperative clinical variables. Only a subgroup of patients was used to examine the association of use of ACEi with new-onset renal failure, because this variable was defined in the database only after 2004. The receiver operating characteristic (ROC) curve was used to assess the predictive accuracy of each logistic regression model. A bootstrap procedure was used for random sampling with replacement from the original data, and 200 bootstrap repetitions were performed. The 95% confidence interval (CI) of the ROC curve was obtained from the 2.5th and 97.5th percentiles of the bootstrap sampling distribution.
Nonparsimonious Cox proportional hazards models were used to examine the association between preoperative ACEi use and long-term outcomes, after adjustment for preoperative clinical characteristics. The validity of the assumption of proportional hazards was assessed through use of the time-dependent covariate test. For each covariate, interaction with time was expressed as the product of the covariate multiplied by log(time), and this interaction term was tested in the model. If the time interaction for a covariate was significant, that covariate was modeled as time-dependent by including both the covariate and its time interaction in the model. This approach allowed valid modeling of nonproportional predictors [7]. Adjusted survival curves were plotted using the corrected group prognosis method of Ghali and colleagues [8].
All analyses were done with SAS version 8.2 (SAS Institute, Cary, NC). The authors of the present article had full access to all data and take responsibility for the integrity of the data, and have read and agree with the contents of the article as written. Although the study included longitudinal data obtained from the Population Health Research Unit at Dalhousie University, the observations and opinions expressed are those of the authors and do not represent those of the Population Health Research Unit.
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Results
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A total of 5,986 patients underwent isolated CABG at our institution during the study period. Of these, 40 patients who were nonresidents of Nova Scotia or who were ineligible for provincial medical insurance were excluded. Of the final study population of 5,946 patients, 3,262 (55%) had preoperative ACEi therapy and 2,684 (45%) did not. The median follow-up periods were 3.6 years (interquartile range [IQR], 1.6 to 5.5 years) and 4.2 years (IQR, 1.9 to 6.8 years) for patients who underwent CABG with or without preoperative ACEi therapy, respectively.
Clinical Characteristics of Patients
The baseline characteristics of the patients in the study are shown in Table 1. As compared with patients undergoing surgery without preoperative ACEi therapy, those undergoing surgery with preoperative ACEi therapy were more likely to have hypertension, diabetes, heart failure, an ejection fraction of less than 40%, and recent MI. They were also more likely to have been receiving concomitant statin therapy or to have peripheral vascular or cerebrovascular disease. In contrast, patients with preoperative ACEi treatment were less likely to undergo urgent or emergent surgery, and were less likely to have preoperative renal failure. In general, those undergoing CABG with preoperative ACEi treatment had greater operative risk, as evidenced by a higher mean logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) than those not treated preoperatively with an ACEi. Intraoperatively, patients undergoing CABG with preoperative ACEi therapy had similar cross-clamp and CPB times, but were more likely to leave the operating room on inotropic support or with an IABP (Table 1). None of the candidate variables for multivariable modeling exceeded the threshold for multi-collinearity.
Clinical Outcomes
Patients undergoing CABG with or without preoperative ACEi treatment had similar rates of in-hospital mortality, perioperative MI, stroke, and new-onset renal failure. The proportion of patients requiring a prolonged stay in the ICU (more than 72 hours) was similar in the two groups, as was the median hospital length of stay for the two groups (Table 2). After differences in baseline characteristics were taken into account, preoperative ACEi use did not emerge as an independent predictor of in-hospital mortality (odds ratio [OR], 1.1; 95% CI = 0.8 to 1.4; p = 0.76), of a prolonged (more than 72 hours) ICU stay (OR, 0.9; 95% CI = 0.7 to 1.0; p = 0.09), or of new-onset renal failure (OR, 0.7; 95% CI = 0.5 to 1.1; p = 0.09) (Fig 1).
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Fig 1. Risk-adjusted effect of preoperative angiotensin-converting enzyme inhibitor (ACEi) use on in-hospital and long-term outcomes after coronary artery bypass grafting. (ACS = acute coronary syndrome; CI = confidence interval; HF = heart failure; ICU = intensive care unit.)
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When examining its effect on long-term outcomes, preoperative ACEi use was found to have no independent association with long-term survival (hazard ratio [HR], 1.0; 95% CI = 0.9 to 1.2; p = 0.54) or freedom from acute coronary syndrome (HR, 0.9; 95% CI = 0.8 to 1.0; p = 0.07). However, preoperative ACEi use was associated with an increased risk of readmission for heart failure (HR = 1.2, 95% CI = 1.1 to 1.4; p = 0.007) over the follow-up period (Fig 1). The percent freedom from readmission for heart failure for patients undergoing CABG with or without ACEi therapy was the same at 30 days (97.8% vs 97.3%) and at 1-year (94.4% vs 93.3%) after CABG. The adjusted curves demonstrating similar freedom from mortality over time in patients undergoing CABG with or without preoperative ACEi use are shown in Figure 2
. The complete logistic regression and Cox proportional hazards models are included for reference in Appendix 2, at www.cdha.nshealth.ca/discovery-innovation/documents.
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Fig 2. Risk adjusted freedom from mortality with and without preoperative angiotensin-converting enzyme inhibitor (ACEi) therapy.
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Comment
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This large observational study found no association between preoperative ACEi use and adverse in-hospital outcomes including mortality, prolonged ICU stay, and new-onset renal failure after CABG. Furthermore, preoperative ACEi use was not associated with long-term survival or freedom from acute coronary syndrome, but was associated with an increased risk of readmission to the hospital for heart failure.
The use of ACEi has become ubiquitous among patients with coronary artery disease (CAD), and these medications were among the three most prescribed medications in the United States in 2010 [9]. Given the proven benefits of ACEi among patients with atherosclerosis and stable CAD, it would appear intuitive that these benefits would extend to patients undergoing CABG [10–13]. Several mechanisms of benefit of ACEi have been suggested, including the ability of these medications to mitigate endothelial dysfunction, suppress saphenous vein graft hyperplasia, and reduce ischemia-reperfusion injury [14–16]. By comparison, excessive hypotension, high vasopressor requirements, and impaired renal function have been suggested as mechanisms of increased harm in the CABG population.
The literature relating to the use of ACEi in cardiac surgery is contradictory. Two small (fewer than 160 patients) randomized trials identified a clinical benefit of ACEi therapy in the setting of CABG [17, 18]. In contrast, Rouleau and coworkers reported in the sizeable Ischemia Management With Accupril Post Bypass Graft Inhibition of Angiotensin-Converting Enzyme (IMAGINE) Trial (n = 2,553) that routine early initiation of ACEi therapy did not improve clinical outcomes at up to 3 years after CABG, and actually increased adverse events in the first 3 months postoperatively [19]. Notably, this study only included "low-risk" patients undergoing CABG, and the doses of quinapril used in the study led to a higher incidence of hypotension and may therefore have been excessive.
Several retrospective observational studies found a benefit for or neutral association of ACEi therapy with outcomes of cardiac surgery [20–22]. Benedetto and colleagues observed that ACEi therapy before CABG reduced postoperative troponin release [4], and two other studies noted a reduction in acute kidney injury in patients receiving ACEi therapy [23, 24]. In contrast, several studies suggested that preoperative administration of ACEi in patients undergoing CABG contributed to a vasoplegic state postoperatively, leading to higher vasopressor requirements and resulting in hypotension and renal impairment [5, 25–27]. More recently, Miceli and colleagues reported a large observational study using propensity score matching in patients undergoing CABG at a single institution in England between 1996 and 2008 [28]. They found that preoperative ACEi therapy was associated with an increased risk of death, postoperative inotropic support, renal dysfunction, and atrial fibrillation. The editorial accompanying their report [29] raised the question of the applicability of these findings to a cohort at higher risk. Presumably, if ACEi use was detrimental in the low-risk patient, its application in the higher risk patient could be even more deleterious. The overall rate of mortality in the study by Miceli and colleagues was low, at 1%, whereas our patients undergoing isolated CABG were at moderately increased risk, with a mean logistic EuroSCORE of 6% and an in-hospital mortality of 3%. Despite the increased risk profile of our patient cohort, we did not find ACEi use to be detrimental. The absence of a deleterious effect of preoperative ACEi use in high-risk cardiac surgical patients has been corroborated by Rady and Ryan [21], who showed no independent association between preoperative ACEi use and mortality in a large (n = 1,650) group of patients with an ejection fraction of less than 35%.
To our knowledge, our study is one of the first to report on the long-term effect of preoperative ACEi use on cardiac surgical outcomes. We found that preoperative ACEi therapy was associated with an increased risk of readmission to the hospital for heart failure following CABG. It is possible that patients receiving ACEi in our study had more extensively remodeled ventricles at baseline, with greater end-systolic indices. It is known that CABG in such a setting may not result in reverse remodeling [30]. In view of this, adjusting outcomes on the basis of ejection fraction alone would not control for this confounding variable. Alternatively, it may be that CABG in the two groups in our study had differing effects on reverse remodeling as the result of unmeasured confounding variables such as differences in viability, inducible ischemia, and the completeness of revascularization. The excess in readmissions for heart failure over the entire follow-up period of our study was not seen at 30 days or at 1 year, suggesting that it may be more indicative of progressive disease rather than of an increased risk of early readmission for heart failure caused by preoperative use of ACEi.
Our study has certain limitations that should be considered. Most importantly, it was observational, and despite the consideration of a wide array of clinical predictors in our analyses, the possibility remains of bias from unmeasured confounders. In addition, we did not have available information about the specific ACEi used, its dosage, whether it was withheld for a specific period preoperatively, whether its prescription was for a long duration, or compliance with its prescribed use. Despite these limitations, this study provides valuable data that have been largely lacking in the cardiac surgical literature about the safety of preoperative ACEi use.
In conclusion, we found that patients undergoing CABG with preoperative ACEi treatment presented with more comorbidities and worse systolic function. After adjusting for baseline differences, no association was found between preoperative ACEi therapy and adverse in-hospital outcomes or long-term survival after CABG. Preoperative ACEi therapy appears to be safe in patients undergoing CABG surgery.
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Abstract
Introduction
